Ethical and methodological concerns have been expressed about studies designed to evaluate invasive therapeutic procedures. Can such studies meet the same standards demanded of those, for example, involving pharmaceutical agents? The proposed project addresses the interplay and, at times, the apparent conflict between ethical standards and standards for methodological quality of studies of invasive procedures, with an eye to reducing such conflict by ethical analysis. This 3-year project will produce a set of consensus standards for good research practice that would have to be met to design and conduct methodologically valid and ethically sound randomized trials of invasive therapeutic procedures. After assembling published policies and literature and subjecting them to an international Delphi process, we will create a comprehensive set of standards for assuring and assessing the methodological and ethical quality of trials of invasive therapeutic procedures (aim 1), refine the standards until they can be applied reliably to existing randomized trials by different raters (aim 2), apply the standards to influential randomized trials of invasive therapeutic procedures conducted after 1991 (the year the Common Rule was adopted by 15 US federal agencies) in order to determine the nature and the surmountability of the methodological and ethical challenges they faced (aim 3), develop consensus on realistic standards by presenting the results of the systematic assessment of trials to a panel of interventionists, ethicists, methodologists, and public representatives (aim 4), and report the finalized standards in the peer-reviewed literature (aim 5). Sources of material will include research ethics policies, textbooks and indexed medical literature, trial protocols, informed consent forms and other internal documents of particular trials, evidence supporting the influence exerted by particular trials (newspaper articles, lawsuits, article citation rates), and the insights and opinions of national and international experts (interventionists, methodologists, and ethicists). Research methods include literature searches conducted with state-of-the-art Cochrane Collaboration algorithms, a web-based international Delphi process, assessment of inter-rater reliability in the application of the methodological and ethical standards to published reports of trials, and face to-face consensus-building methods. The use of the resulting standards in planning and design will lead to the fielding of trials that will yield the least-biased estimates of treatment effects while satisfying fundamental moral commitments to respect for persons, beneficence, and justice. The project will result in substantial and much needed improvements in the methodological and ethical quality of trials performed to evaluate invasive therapeutic procedures in humans. PUBLIC HEALTH RELEVANCE: The project will result in substantial and much-needed improvements in the methodological and ethical quality of trials performed to evaluate invasive therapeutic procedures in humans.